2-BENZOHETEROCYCLYLOXY OR THIOPROPANOLAMINE DERIVATIVES WITH ADRENO RECEPTOR AGONIST ACTIVITY

Abstract: 2-Benzoheterocyclyloxy or thiopropanolamine derivatives of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein, R<o> represents a moiety of formula (a), wherein one of X<1> or X<2> represents NH and the other of X<1> or X<2> represents NH, O or S and T represents hydrogen or one, two or three substituents selected from the list consisting of: hydroxy, amino, alkylamino, dialkylamino, alkylsulphonamido, arylsulphonamido, amidoformyl, halogen and alkoxy; X represents O or S; R<1> and R<1a> each independently represents hydrogen or an alkyl group; R<2> represents OCH2CO2H, or an ester or amide thereof, or R<2> represents a moiety of formula (b), wherein R<4> represents hydrogen, alkyl, hydroxyalkyl or cycloalkyl and R<5> represents hydroxy, alkoxy, hydroxyalkyloxy or cycloalkyloxy or R<5> represents hydrogen, alkyl, substituted alkyl, cycloalkyl or aryl or R<5> together with OR<4> represents O(CH2)nO wherein n is 2, 3 or 4; and R<3> represents hydrogen, halogen, alkyl or alkoxy or R<3> together with R<2> represents a moiety of formula (c), or an ester or amide thereof; a process for the preparation of such a compound, a pharmaceutical composition comprising such a compound and the use of such a compound in medicine. The claimed compounds are adreno receptor agonists.

Description: 2-BENZ0HETER0CYCLYL0XY OR THIO PROPANOLAMINE DERIVATIVES WITH ADRENO RECEPTOR AGONIST ACTIVITY This invention relates to novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to die 5 use of such compounds and compositions in medicine and agriculture. Offenlegungschrift 2905877 discloses certain 1-amino heterocyclyloxy-2- propanol derivatives which are stated to have inter alia beta adrenergic blocking activity. United Kingdom Patent Application, Publication Number 2014146 A 10 discloses certain etherified hydroxy - benzodiheterocyclic derivatives which are stated to have long lasting cardioselective beta - receptor blocking activity and alpha receptor blocking activity. United States Patent Number 4367235 discloses certain 2-benzimidazolinone compounds which are stated to have marked beta - receptor blocking activity. 15 International Patent Application, Publication Number 94/02493 discloses certain phosphonated arylethanolamine derivatives which are stated to have inter alia good anti-hyperglycaemic and/or anti-obesity activity coupled with especially good selectivity from cardiac and tremorigenic side effects. It has now surprisingly been discovered that a particular series of novel 20 2-benzoheterocyclyl-oxy or thio propanolamine derivatives have good β3- adrenoreceptor agonist activity and in particular showing good selectivity for β - adrenoreceptors over the βj- or β2-adrenoreceptors, to the extent that these compounds are antagonists of the βj- and β2-adrenoreceptors. These compounds are indicated to have good anti-hyperglycaemic and/or anti-obesity activity coupled with 25 especially good selectivity from cardiac and tremorigenic side effects. These compounds are also indicated to have potential in the treatment of gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis and duodenitis, intestinal ulcerations, including inflammatory bowel disease, and irritable bowel syndrome and also for the treatment of gastrointestinal ulcerations, especially 30 when induced by non-steroidal anti-inflammatory drugs or corticosteroids. These compounds may also be of use in increasing the high-density- lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in human blood serum and are therefore of potential use in the treatment and/or prophylaxis of atherosclerosis. They are also indicated to be useful 35 for the treatment of hyperinsulinaemia. They are also indicated to be useful for the treatment of depression. These compounds also have potential as growth promoters for livestock and for decreasing birth mortality rate and increasing the post-natal survival rate in livestock. Accordingly the present invention provides a compound of formula (I): 1a OH R R J R°-X-CH.-CH-CH ? -NH-CR -CH 2 • # * (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein, R° represents a moiety of formula (a): (a) wherein one of χl or X^ represents NH and the other of X* or X^ represents NH, O or S and T represents hydrogen or one, two or three substitutents selected from the list consisting of: hydroxy, amino, alkylamino, dialkylamino, alkylsulphonamido, arylsulphonamido, amidoformyl, halogen and alkoxy; X represents O or S; R! and R^ a each independently represents hydrogen or an alkyl group; R2 represents OCH2CO2H, or an ester or amide thereof, or R^ represents a moiety of formula (b): (b) wherein R^ represent hydrogen, alkyl, hydroxyalkyl or cycloalkyl and R^ represent hydroxy, alkoxy, hydroxyalkyloxy or cycloalkyloxy or R^ represents hydrogen, alkyl, substituted alkyl, cycloalkyl or aryl or R^ together with OR'* represents O(CH2>nO wherein n is 2, 3 or 4; and R3 represents hydrogen, halogen, alkyl or alkoxy or R^ together with R^ represents a moiety of formula (c): (c) or an ester or amide thereof. Suitably, R^ is an alkyl group. When R! is alkyl, it is favourably a Cj.g alkyl group, especially a methyl group. Suitably, R^ a represents hydrogen. Suitably, X* represents NH. Suitably, X^ represents NH. Preferably, X^ and X^ each represents NH. Suitably.T represents hydrogen. In one aspect, R^ represents OCH2CO2H, or an ester or amide thereof. In one aspect, R^ represents a moiety of formula (b). In one aspect of the invention, R^ together with R^ represents a moiety of formula (c). Preferably, R^ is a moiety of formula (b). Preferably, R^ is hydrogen. Favourably, R^ represent hydrogen or alkyl, especially alkyl. Suitably, R^ represents hydroxy, alkoxy, hydroxyalkyloxy or cycloalkyloxy. Suitably, R^ represents hydrogen, alkyl, substituted alkyl, cycloalkyl or aryl. Favourably, R^ represents hydroxy, alkoxy or hydroxyalkyloxy. Suitably, in the hydroxyalkyloxy group represented by R^ the hydroxy group is substituted on the terminal carbon atom of the alkyl group, for example as in a 2- hydroxypropyloxy group. Preferably, R^ represents alkoxy. Preferably, R^ represent alkyl, especially C .Q alkyl, for example ethyl, and R5 represent alkoxy, -especially C\. alkoxy, for example ethoxy. In another aspect, R^ is alkyl, for example ethyl, and R^ is hydrogen. Suitably, X represents O. The compounds of formula (I) have one or two asymmetric carbon atoms, marked with an asterisk (*) or two asterisks (**) in the formula. These compounds may therefore exist in up to four stereoisomeric forms. The present invention encompasses all stereoisomers of the compounds of the general formula (I) whether free from other isomers, or admixed with other isomers in any proportion, such as mixtures of diastereoisomers and racemic mixtures of enantiomers. Preferably, the asymmetric carbon atom indicated by a single asterisk (*) is in the S -configuration. Preferably, the asymmetric carbon atom indicated by two asterisks (**) is in the R-confϊguration. One suitable form of a compound of formula (I) is a mixture of the SR and RS enantiomers. In a particular aspect the present invention provides a compound selected from the list consisting of: (S,R)4-(2-[2-hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazol-4- yloxy)propylamino]propyl)phenoxy)acetic acid, methyl ester, S,R) 4-(2-[2-hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazol- 4- yloxy)propylamino]propyl)phenoxy)acetic acid; (S,R)-4-[2-hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazol-4- yloxy)propylamino]propyl)phenoxymethylphosphonic acid, diethyl ester; and especially, (S, R) 4-[2-hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazol-4- yloxypropylamino]propyl)phenoxymethylphosphonic acid, ethyl ester; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, One favoured form of a compound of formula (I) is the SR enantiomer. The term 'alkyl' when used alone or when forming part of other groups (such as the 'alkoxy' group) includes straight- or branched-chain alkyl groups containing 1 to 12 carbon atoms, suitably 1 to 6 carbon atoms, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group. The term 'cycloalkyl' includes C3_g cycloalkyl groups, especially C5 or Cg cycloalkyl groups. When used herein the term "halogen" refers to fluorine, chlorine, bromine and iodine, preferably chlorine. Suitable pharmaceutically acceptable esters of carboxyl groups include alkyl esters, especially Cj.g alkyl esters such as methyl. Suitable pharmaceutically acceptable amides are those of formula -CONR s R t wherein R s and R l each independently represent hydrogen, alkyl or alkoxyalkyl. Suitable pharmaceutically acceptable salts include acid addition salts, salts of carboxy groups and salts of phosphonic acid groups. Suitable pharmaceutically acceptable acid addition salts include salts with inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid, or with organic acids such, for example as methanesulphonic acid, toluenesulophonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid or acetylsalicylic acid. Suitable pharmaceutically acceptable salts of carboxy groups or phosphonic acid groups include metal salts, such as for example aluminium, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with C\. alkylamines such as triethyla ine, hydroxy-Cj.g alkylamines such as 2-hydroxyethylamine, bis-(2- hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine or quinoline. Suitable pharmaceutically acceptable solvates are conventional solvates, preferably hydrates. In a further aspect the invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable solvate thereof, which process comprises reacting a compound of formula (II) with phosgene: (ID wherein R , R a , R^, R3 and X are as defined in relation to formula (I), one of X^ or X^ represents NH2 and the other of X^ or X^ is selected from NH2 > OH or SH and T * represents T as defined in relation to formula (I) or a protected form thereof; and thereafter, if necessary, carrying out one or more of the following optional steps: (i) converting one compound of formula (I) to another compound of formula (I); and (ii) preparing a pharmaceutically acceptable acid addition salt of a compound of formula (I) or a pharmaceutically acceptable solvate thereof. The reaction between the compound of formula (II) and phosgene may be carried out in any suitable solvent, generally an aqueous solvent such as aqueous hydrogen chloride, at any temperature providing a suitable rate of formation of the required product, usually at a low to ambient temperature, such as in the range of from 0°C to 15°C, for example at 5°C. A compound of formula (II) may be prepared by reducing a compound of formula (III): (HI) wherein R 1 , R la , R 2 , R 3 , T' and X are as defined in relation to the compounds of formula (II), one of X 5 or X 6 represents NO2 and the other of X 5 and X > represents NH2, ORPl or SRPi, wherein RPl represents hydrogen or a protecting group, and thereafter removing any protecting group RP . The reduction of the compound of formula (III) may be carried out using any suitable reduction procedure, usually catalytic hydrogenation for example by using a 10% palladium on carbon catalyst optionally in the presence of ammonium formate. Suitable reduction conditions include using an alkanol solvent such as methanol, preferably deoxygenated with for example carbon dioxide, at any temperature providing a suitable rate of formation of the required product, usually at a low to ambient temperature, conveniently at ambient temperature. Suitably, RP represents a protecting group such as a benzyl group or, especially when either of X^ or X^ is ORPl or SRP , a substituted benzyl group such as a 4-methoxybenzyl group, which may be removed using any conventional procedure, for example catalytic hydrogenolysis, for removal of benzyl from oxygen, or treatment with mercuric acetate, for removal of 4-methoxybenzyl from sulphur. The compound of formula (III) may be prepared by reacting a compound of formula (IV): (IV) wherein T', X, X^ and X*> are as defined in relation to formula (II), with a compound of formula (V): ( V) wherein Rl, Rr- and R 3 are as defined in relation to formula (I). The reaction between compounds of formulae (IV) and (V) may be carried out in any suitable solvent, such as methanol, at any temperature providing a suitable rate of formation of the required product, generally at an elevated temperature such as the reflux temperature of the solvent; preferably under an inert atmosphere such as nitrogen. A compound of formula (IV) may be prepared by reacting an activated form of a compound of formula (IVA): wherein X, X^, χ6 and T are as defined in relation to formula (IV), with a compound of formula (IVB): * L— CH 2 — CH— -CH 2 ^ (IVB) wherein L^ represents a leaving group. A suitable activated form of a compound of formula (IVA) is an ionic form, such as an alkali metal salted form, for example a potassium salted form. An activated form of a compound of formula (IVA) may be prepared by use of the appropriate conventional procedure, for example a salted form may be prepared by treating the compound of formula (IVA) with a base such as an alkali bicarbonate, for example potassium bicarbonate. Suitably, L represents a tosylate or a 3-nitrosulphonyl group. The reaction between the compounds of formulae (IVA) and (IVB) may be carried out in an aprotic solvent such as acetone at any temperature providing a suitable rate of formation of the required product, generally at an ambient to elevated temperature, suitably an elevated temperature, such as the reflux temperature of the solvent. A compound of formula (V) may be prepared by the hydrogenolysis of a compound of formula (VI): wherein R 1 , R 2 and R 3 are as defined in relation to formula (I) and the **CH carbon and ***CH carbon atoms are chiral carbon atoms. Suitably, catalytic hydrogenolysis is used, using for example 10% palladium on charcoal in the presence of ammonium formate, suitably in an alkanolic solvent such as methanol, at any temperature providing a convenient rate of formation of the required product, for example at ambient temperature; preferably the reaction is caπied out in an inert atmosphere, generally under nitrogen . The compound of formula (VI) may be prepared by stereoselective reduction of a compound of formula (VII): (VII) wherein Rl, R 2 and R 3 are as defined in relation to formula (I) and the ***CH carbon is a chiral carbon. The reduction of the compound of formula (VII) may be carried out using catalytic reduction in the presence of hydrogen. A preferred catalyst is platinum oxide. Suitable reduction conditions include using an alkanol solvent such as methanol or ethanol, at any temperature providing a convenient rate of formation of the required product, conveniently at ambient temperature using a pressure of 1-5 atmospheres of hydrogen. The compound of formula (VII) may be prepared by reacting a compound of formula (VIII): (VIII) wherein Rl, R 2 and R 3 are as defined in relation to formula (I), with R-α-methylbenzylamine. The reaction between compounds of formulae (VIII) and R-α-methylbenzylamine may be carried out under conventional amination conditions, for example in a solvent such as methanol or toluene. Conveniently, the compound of formula (VII) is prepared in-situ by reacting a compound of the above defined formula (VIE) with R-α-methylbenzyl amine and thereafter reducing the compound of formula (VII) so formed using reaction conditions and catalysts as described above. The compounds of formula (VIII) wherein R 2 represents OCH2CO2H or an an ester or amide thereof or wherein R2 represents a moiety of the above defined formula (b) wherein R^ represent hydroxy, alkoxy, hydroxyalkyloxy or cycloalkyloxy or R^ together with OR^ represents O(CH2) n O, are known compounds or they may be prepared by processes analogous to those used to prepare such compounds, for example they may be prepared according to methods disclosed in European Patent Application, Publication Number 0023385 or International Application number WO 94/02493. A compound of formula (VIII) such as those wherein R 2 represents a moiety of the above defined formula (b) wherein R^ represent hydrogen, alkyl, substituted alkyl, cycloalkyl or aryl may be prepared by reducing a compound of formula (IX): (IX) wherein R* and R 3 are as defined in relation to formula (I) and as stated R 2 is as defined in relation to the required compounds of of formula (VIII). The reduction of the compound of formula (IX) may conveniently be carried out using iron powder in the presence of acetic acid in an aqueous solvent such as aqueous methanol, at any temperature providing a suitable rate of formation of the required product, generally at an elevated temperature and conveniently at the reflux temperature of the solvent. A compound of formula (IX) may be prepared by reacting a compound of formula (X): (X) wherein, R 2 and R 3 are as defined in relation to formula (IX), with nitroalkane. Generally, the carbon atom of the -CHO group in the compound of formula (X) is in an activated form, a suitable activated form being provided by forming an imine of the said carbonyl group: The imine may be prepared by reacting the compound of formula (X) with an amine, suitably a primary alkyl amine such as n- butylamine. The reaction of the compound of formula (X) and the amine may be carried out in any suitable solvent, such as toluene, at any temperature providing a suitable rate of formation of the required product, generally at an elevated temperature such as the reflux temperature of the solvent; and preferably in the presence of a catalytic amount of toluenesulphonic acid. The reaction between the compound of formula (X), and when it is in the form of an imine and nitroalkane may be carried out in glacial acetic acid, preferably in the presence of an ammonium acetate catalyst, generally at an elevated temperature such as in the range of from 60°C to 120°C, for example 100°C. A compound of formula (X) may be prepared from a compound of formula (XI): (XI) wherein R^ is as defined in relation to formula (IX) and L^ is a leaving group or atom, generally a fluorine atom, with an activated form of a compound of formula (XII): o II HO-CH 2 -P-OR 4 R (XII) wherein R^ and R^ are as defined in relation to formula (I). A suitable activated form of a compound of formula (XII) is an ionic form, such as a salted form, for example an alkali metal salted form. An activated form of a compound of formula (XII) may be prepared by use of the appropriate conventional procedure, for example a salted form may be prepared by treating the compound of formula (XII) with a base such as an alkali metal hydride, for example sodium hydride. The reaction between the compounds of formulae (XI) and (XII) may be carried out in any suitable solvent, generally an aprotic solvent such as dimethylformamide or N-methylpyrrolidinone at a low to ambient temperature, for example in the range of from - 15°C to 20°C, such as 5°C. A compound of formula (I), wherein R* a represents hydrogen, or a pharmaceutically acceptable salt, ester or amide thereof or a pharmaceutically acceptable solvate thereof, may also be prepared by reducing a compound of formula (XIII): (XIII) wherein R°, Rl, R3 and X are as defined in relation to formula (I) and R 2 ' represents R 2 as defined in relation to formula (I) or a protected form thereof; and thereafter, if necessary, carrying out one or more of the following optional steps: (i) converting one compound of formula (I) to another compound of formula (I); and 14 (ii) removing any protecting group; and (iii) preparing a pharmaceutically acceptable salt, ester or amide thereof of a compound of formula (I) or a pharmaceutically acceptable solvate thereof. The reduction of the compound of formula (XIII) may be carried out using any suitable reduction procedure, for example by using catalytic reduction. Suitable catalysts include platinum oxide or 10% palladium on charcoal. Suitable reduction conditions include using an alkanolic solvent such as methanol, at any temperature providing a convenient rate of formation of the required product, for example when using the platinum catalyst the reaction may conveniently be carried out at ambient temperature or when using the palladium catalyst the reaction may be carried out at a medium temperature such as 50°C, under a pressure of 1-5 atmospheres of hydrogen. For compounds of formula (I) wherein R 2 represents a moiety of the above defined formula (b), R 2 ' generally represents a protected form of R 2 , for example a benzylated form, which may be removed by use of any conventional method, thus the benzylated form may be removed by use of hydrogenolysis using ammonium formate in the presence of a 10% palladium on carbon catalyst. The compound of formula (XIII) may be prepared by reacting a compound of formula (XIV): OH R°-X-CH 2 -CH-CH 2 -NH 2 (XIV) wherein R° and X are as defined in relation to formula (I) with a compound of the above defined formula (VIII). The reaction between compounds of formulae (VIII) and (XIV) may be carried out under conventional amination conditions, for example in a solvent such as toluene or, preferably, methanol. Conveniently, the compound of formula (XIII) is prepared in-siru by reacting a compounds of the above defined formulae (VIII) and (XIV) under reductive amination conditions which includes reaction in an alkanolic solvent, such as methanol, in the presence of a suitable reduction catalyst, for example those described above for the reduction of the compound of formula (XIII). A compound of formula (XIV) may be prepared by reacting a compound of formula (XV) with phosgene: (XV) wherein RP, X, X 3 , X^ and T are as defined in relation to the compounds of formula (II); and thereafter, if required, removing any protecting group. Suitably, RP represents a protecting group, such as a benzyl group which may conveniently be removed by use of catalytic hydrogenolysis, for example by use of ammonium formate in the presence of a 10% palladium on carbon catalyst, as described above. Generally, when T in the required compound of formula (XIV) represents OH or NH2 then T' represents a protected form thereof, such as a benzylated hydroxy group or an acylated amino group. The conversion of T * to the corresponding T, by removal of the protecting group, is carried out using the appropriate conventional procedure. The reaction of the compound of formula (XV) with phosgene may be carried out under analogous conditions to those disclosed above for the reaction of the compound of formula (II) with phosgene. A compound of formula (XV) may be prepared by reducing a compound of formula (XVI): (XVI) wherein RP, X, X^, χ6 and T are as defined in relation to formula (III). The reduction of the compound of formula (XVI) is conveniently carried out using an analogous procedure to that described above for the reduction of the compounds of formula (III) usually catalytic hydrogenation for example by using a 10% palladium on carbon catalyst optionally in the presence of ammonium formate. Suitably in X^or χ6, RPl represents a protecting group such as a benzyl group which may be removed using any conventional procedure, for example catalytic hydrogenolysis, for removal of benzyl from oxygen, or treatment with mercuric acetate, for removal of benzyl from sulphur. The compounds of formula (XVI) are known compounds or they may be prepared according to methods used to prepare known compounds, for example those methods disclosed in United Kingdom Patent Application, Publication Number 2014146 A. The compounds of formula (IV), wherein X^ and X > each independently represent NH2, are known commercially available compounds or they may be prepared by processes analogous to those used to prepare such compounds, for example they may be prepared according to methods disclosed in Appl. Radiab. Isot., 1991, 42(7), 621-628. The compounds of formula (IVA) are either known commercially available compounds or known compounds prepared according to published methods or by use of analogous methods to the published methods, thus the compounds wherein X^ is SH, χ6 is NH2 and T is H may be prepared according to methods disclosed in Phammzie, 1986, 41(12), 830. The compounds of formula (IVB) are known commercially available compounds. The compounds of formula (XII) are known compounds or they may be prepared by processes analogous to those used to prepare known compounds, for example the compounds of formula (XII) may be prepared according to methods disclosed in Phosphorus and Sulphur, 1978, 5, 455. Suitable conversions of one compound of formula (I) into another compound of formula (I) include converting one group OR 4 into another group OR 4 and/or converting one group R^ into another group R^. Suitable conversions of one group OR 4 into another group OR * include: (i) converting OR'* as hydroxy into OR 4 as alkoxy; (ii) converting OR** as alkoxy into OR * as hydroxy; (iii) convening OR 4 as alkoxy into OR** as another alkoxy group. The abovementioned conversion (i) may be carried out under conventional phosphonate alkylation methods, using for example the appropriate alcohol (R 4 OH) in the presence of hydrogen chloride. The abovementioned conversion (ii) may be carried out using conventional phosphonate hydrolysis methods, for example by treating the appropriate compound of formula (I) with an alkaline metal hydroxide, such as sodium hydroxide. The abovementioned conversion (iii) may be carried out by first converting OR' as alkoxy into OR 4 as hydroxy using the conditions set out in respect of the abovementioned conversion (ii), followed by converting the hydroxy group so formed into another alkoxy group, using the conditions set out in respect of the abovementioned conversion (i). The abovementioned conversion (iii) is of particular use for preparing compounds of formula (I) wherein OR** represents methoxy: such compounds are generally prepared from compounds of formula (I) wherein OR 4 represents an alkyloxy group other than methoxy (suitably ethoxy) by first hydrolysing the relevant OR 4 group (via conversion (ii)) to prepare a compound of formula (I) wherein OR'* represents hydroxy and thereafter methylating (via conversion (i)) to provide the required compound wherein OR * represents methoxy. Suitable conversions of one group R^ into another group R^ include analogous conversions to those mentioned above in regard to converting one group OR 4 into another group OR 4 . The protection of any reactive group or atom, may be carried out at any appropriate stage in the aforementioned processes. Suitable protecting groups include those used conventionally in the art for the particular group or atom being protected. Protecting groups may be prepared and removed using the appropriate conventional procedure. A leaving group or atom is any group or atom that will, under the reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Suitable examples of such groups unless othewise specified are halogen atoms, mesyloxy groups and tosyloxy groups. The salts, esters, amides and solvates of the compounds mentioned herein may be produced by methods conventional in the art: For example, acid addition salts may be prepared by treating a compound of formula (I) with the appropriate acid. Esters of carboxylic acids may be prepared by conventional esterification procedures, for example alkyl esters may be prepared by treating the required carboxylic acid with the appropriate alkanol, generally under acidic conditions. Amides may be prepared using conventional amidation procedures, for example amides of formula CONR s R l may be prepared by treating the relevant carboxylic acid with an amine of formula HNR s R l » wherein R s and R l are as defined above. Alternatively, a C\. alkyl ester such as a methyl ester of the acid may be treated with an amine of the above defined formula HNR s R l to provide the required amide. Compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof; or a pharmaceutically acceptable solvate thereof, produced by the above processes, may be recovered by conventional methods. If required mixtures of isomers of the compounds of the invention may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent. Suitable optically active acids which maybe used as resolving agents are described in Topics in Stereochemistry', Vol. 6, Wiley Interscience, 1971 , Allinger, N.L. and Eliel, W.L. Eds. Alternatively, any enantiomer of a compound of the invention may be obtained by stereospecific synthesis using optically pure starting materials of known configuration. The absolute configuration of compounds may be determined by conventional X-ray crystallographic techniques. As previously indicated, the compounds of the present invention have valuable pharmacological properties: The present invention accordingly provides a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance. In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of hyperglycaemia in human or non-human animals. The present invention further provides a compound of formula (I), or pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of obesity in human or non-human animals. In addition the present invention provides a compound of formula (I), or pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis and duodenitis, intestinal ulcerations, including inflammatory bowel disease, and irritable bowel syndrome and also for the treatment of gastrointestinal ulcerations, especially when induced by non-steroidal anti-inflammatory drugs or corticosteroids. Finally, the present invention provides a compound of formula (I), or pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, for use in increasing the high-density-lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in human blood serum, in particular in the treatment and/or prophylaxis of atherosclerosis, and in the treatment of hyperinsulinaemia or depression. A compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor. As used herein the term "pharmaceutically acceptable" embraces compounds, compositions and ingredients for both human and veterinary use: for example the term "pharmaceutically acceptable salt" embraces a veterinarily acceptable salt. The composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use. Usually the pharmaceutical compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection, are also envisaged. Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as powders presented in sachets, may also be used. In accordance with conventional pharmaceutical practice the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant. Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate. Most suitably the composition will be formulated in unit dose form. Such unit dose will normally contain an amount of the active ingredient in the range of from 0.1 to 1000 mg, more usually 2-100 mg or 0.1 to 500 mg, and more especially 0.1 to 250 mg. The present invention further provides a method for treating hyperglycaemia in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, to a hyperglycaemic human or non-human mammal in need thereof. The present invention further provides a method for treating obesity or for the treatment and/or prophylaxis of atherosclerosis in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof. The present invention further provides a method for treating gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis and duodenitis, intestinal ulcerations, including inflammatory bowel disease, and irritable bowel syndrome and also for the treatment of gastrointestinal ulcerations, especially when induced by non- steroidal anti-inflammatory drugs or corticosteroids, in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof. In addition the present invention provides a method for treating for increasing the high-density-lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in human blood serum, in particular in the treatment and/or prophylaxis of atherosclerosis, and in the treatment of hyperinsulinaemia or depression, in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, to a human or non-human mammal in need thereof. The the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of: hyperglycaemia, obesity, gastrointestinal disorders such as peptic ulceration, oesophagitis, gastritis and duodenitis, intestinal ulcerations, including inflammatory bowel disease, and irritable bowel syndrome and also for the treatment of gastrointestinal ulcerations, especially when induced by non-steroidal anti- inflammatory drugs or corticosteroids, for increasing the high-density-lipoprotein (HDL) cholesterol concentration and decreasing the triglyceride concentration in human blood serum, in particular in the treatment and/or prophylaxis of atherosclerosis, and in the treatment of hyperinsulinaemia or depression. Conveniently, the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, and this forms a particular aspect of the present invention. In treating hyperglycaemic or obese humans the compound of formula (I), or a pharmaceutically acceptable salt, ester or amide thereof; or a pharmaceutically acceptable solvate thereof, may be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg. The treatment regimens for treating the abovementioned gastrointestinal disorders atherosclerosis, hyperinsulinaemia and depression are generally as described for hyperglycaemia. In treating non-human mammals, especially dogs, the active ingredient may be adminstered by mouth, usually once or twice a day and in an amount in the range of from about 0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg. In a further aspect the present invention also provides a method for increasing weight gain and or improving the feed utilisation efficiency and/or increasing lean body mass and/or decreasing birth mortality rate and increasing post/natal survival rate: of livestock, which method comprises the administration to livestock of an effective non-toxic amount of a compound of formula (I) or a veterinarily acceptable acid addition salt thereof, or a veterinarily acceptable solvate thereof. Whilst the compounds of formula (I) and the veterinarily acceptable acid addition salts thereof or a veterinarily acceptable solvate thereof, may be administered to any livestock in the abovementioned method, they are particularly suitable for increasing weight gain and/or feed utilisation efficiency and/or lean body mass and/or decreasing birth mortality rate and increasing post-natal survival rate; in poultry, especially turkeys and chickens, cattle, pigs and sheep. In the preceding method the compounds of formula (I) or veterinarily acceptable acid addition salts thereof will normally be administered orally although non-oral modes of administration, for example injection or implantation, are also envisaged. Suitably the compounds are administered in the feed-stuff or drinking water provided for the livestock. Conveniently these are administered in the feed-stuff at from 10-3 ppm - 500ppm of total daily fed intake, more usually O.Olppm to 250ppm, suitably less than lOOppm. The particular formulations used will of course depend upon the mode of administration but will be those used conventionally in the mode of administration chosen. For administration in feed-stuff the drugs are conveniently formulated as a premix in association with a suitable carrier. Accordingly, the present invention also provides a veterinarily acceptable premix formulation comprising a compound of formula (I), or a veterinarily acceptable acid addition salt thereof; or a veterinarily acceptable solvate thereof, in association with a veterinarily acceptable carrier therefore. Suitable carriers are inert conventional agents such as powdered starch. Other conventional feed-stuff premix carriers may also be employed. No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention. The following Examples illustrate the invention but do not limit it in any way. Procedure 1 (S R) 4-[2-[(2-hydroxy-3-(2-amino-3-nitrophenoxy)propyl)amino]-2- propyI]phenoxyacetic acid, methyl ester A mixture of (S)-3-(2-amino-3-nitrophenoxy)-l,2-epoxypropane (2.19g, 10.43 mMol) and (R)-methyl 4-(2-aminopropyl)phenoxyacetate (2.33g, 10.45 mMol) was dissolved in methanol (60ml) and refluxed under a nitrogen atmosphere for 4.5 hours, and then stirred overnight at room temperature. The methanol was evaporated and the residue taken up into dichloromethane (100ml), washed with of water (3 x 75 ml) and dried with anhydrous magnesium sulphate. The dichloromethane was then evaporated. The crude product was purified by chromatography over normal phase silica, eluting with 0 - 6% methanol in dichloromethane to give (S R) 4-[2-[(2-hydroxy-3- (2-amino-3-nitrophenoxy)propyl)amino]-2-propyl]phenoxyacetic acid, methyl ester. δ 1 H(270MHz, CDC1 3 ): 7.75(1H, d, J=8.94Hz); 7.11(2H, d, J=8.80Hz);6.89-6.82(3H, m); 6.57(1H, t, J=6.23Hz); 6.53(s br, exchanges with D 2 O); 4.62(2H, s); 3.99(3H, s); 3.81(3H, s); 2.95-2.87(lH, m); 2.78-2.68(2H, m); 2.67(2H, m); L11(3H, d, J=6.33Hz). Procedure 2 (S R) 4-[2-[2-hydroxy-3-(2-amino-3-nitrophenoxy)propyl-amino]-2- propyI]phenoxymethylphosphonic acid, diethyl ester The title compound was prepared by an analogous method to that described in Procedure 1 from (S)-3-(2-amino-3-nitrophenoxy)-l,2-epoxypropane (140mg, 0.67mMol) and (R)-diethyl 4-(2-aminopropyl)phenoxymethylphosphonate (200mg, 0.66mMol) by heating under reflux in methanol (20ml) for 24h. The solvent was removed under reduced pressure, the residue was taken into ethyl acetate and washed with water (2 x 15ml) and the aqueous extracts back extracted with ethyl acetate (2 x 10ml). The organic extracts were combined, washed with brine (2 x 15ml), dried and the solvent removed under reduced pressure. The crude product was purified by column chromatography eluting with 0-8% methanol in dichloromethane. δ 1 H(270MHz, d 6 -DMSO): 7.65(1H, d, J=8.1Hz); 7.28QH, exchanges with D 2 O); 7.18(2H, d, J=7.4Hz); 7.04(1H, d, J=8.1Hz); 6.97(2H, d, J=7.4Hz); 6.63QH, t, J=8.1Hz); 4.76(2H, exchanges with D 2 O) 4.41 (2H, d, J=10.1Hz); 4.23-4.05(5H, complex multiplet); 3.95(2H, m); 2.90-2.65(4H, complex multiplet); 2.48(1H, q, J=6.8Hz); 1.32(6H, t, J=6.8Hz); 0.99(3H, d, J=6.8Hz). Procedure 3 (S) [3-(BenzyIamino)-2-hydroxypropoxy]-2-amino-3-nitrobenzene A mixture of (S)-3-(2-amino-3-nitrophenoxy)-l,2-epoxypropane (4g, 19.04mMol) and lithium perchlorate (2.03g, 19.04mMol) was dissolved in acetonitrile (70ml). After stirring for 10 minutes, benzylamine (2.04g, 2.08ml, 19.04mMol) was added and the mixture refluxed under a argon atmosphere for 6 hours, and then stirred over night at room temperature. The acetonitrile was evaporated and the residue taken up into ethyl acetate (100ml), washed with water (3x50ml) and dried with anhydrous sodium sulphate. The ethyl acetate was then evaporated. The crude product was purified by chromatography over normal phase silica, eluting with 0-5% methanol in ethyl acetate to give (S)-[3-(benzylamino)-2- hydroxypropoxy]-2-amino-3-nitrobenzene. δ1H (250MHz, CDC1 3 ) 7.78 (IH, d, J=9.28Hz); 7.4 (5H, m); 6.94 (IH, d, J=9.3Hz); 6.60 (IH, t, J=9.4Hz); 6.48 (s, br, exchanges with D 2 O); 4.15 (3H, m); 3.87 (2H, d, J=4.31Hz); 2.95 (IH, m); 2.81 (lH, m). Procedure 4 (S) 4-[2-Hydroxy-3-(phenylmethylamino)propoxy]-2-oxo-2,3-lH- benzoimidazole A mixture of (S)-[3-(benzylamino)-2-hydroxypropoxy]-2-amino-3-nitrobenzene (1.2g, 3.79mMol) and 10% palladium on charcoal (25mg) in ethanol (30ml) was hydrogenated at atmospheric pressure. After 3 hours the reaction mixture was filtered through a short pad of celite and the solvent evaporated to yield a brown oil which was used in the next step without further purification. (S)-[3-(benzylamino)-2-hydroxypropoxy]-2,3-diamino benzene (klg, 3.83mMol) was dissolved in aqueous hydrogen chloride (2 Molar, 30ml); to this was added a further 10ml of water. The solution was cooled to 5°C and phosgene in toluene (1.93M, 9.92ml, 19.15mMol) was added with stirring. The mixture was then stirred overnight before being flushed out for 1 hour with a strong stream of argon. The mixture was neutralised with solid sodium hydrogen carbonate and extracted with dichloromethane (3x25ml). The resulting solution was dried with sodium sulfate and the solvent evaporated. The crude material was purified by chromatography over normal phase silica using 5-20% methanol in ethyl acetate, to give the title compound as brown crystals of m.p.=121-2°C δ H (250MHz, d 6 -DMSO) 10.71 (IH, exchanges with D2O); 10.61 (IH, exchanges with D2O); 7.45 (5H, m); 6.85 (IH, t, J=9.87Hz); 6.61 (2H, ); 4.85 (s, br, exchanges with D 2 O); 4.05 (3H, m); 3.71 (2H, s); 2.65 (2H, m). Procedure 5 (S) 4-(3-Amino-2-hydroxypropoxy)-2-oxo-2,3-lH-benzoimidazoIe (S)-4-[2-Hydroxy-3-(phenylmethylamino)propoxy]-2-oxo-2,3-lH-benzoimida2»le (1.26g, 4.03mMol) was dissolved in methanol (25ml). The solution was cooled and de-aerated with solid CO2. Ammonium formate (5.08g, 80.6mMol) and 10% palladium on carbon (50mg) was added. The mixture was stirred at reflux under an argon atmosphere for 16 hours. The mixture was filtered through a short pad of celite and the methanol evaporated. The ammonium formate was removed by freeze drying, to yield a dark oil. δH 1 (250MHz, d 6 -DMSO) 6.85 (IH, t, J=8.47Hz); 6.64 (2H, m); 4.07 (IH, m); 3.91 (IH, m); 3.75 (IH, ); 3.30 (s, br, exchanges with D2O); 2.70 (2H, m). Example 1 (S R) 4-(2-[2-Hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazoI-4- yloxy)propyIamino]propyI)phenoxy)acetic acid, methyl ester (S, R)-Methyl 4-[2-[(2-hydroxy-3-(2-amino-3-nitrophenoxy) propyl)amino]-2-propyl]phenoxy acetate (0.786g, 1.82 mMol) was dissolved in methanol (100ml), the solution was cooled and de-aerated with solid CO2, ammonium formate (4.5g, 71.43 mMol) and 10% palladium on carbon catalyst (O.lg) was added. The mixture was stirred at room temperature under a nitrogen atmosphere for 19 hours. The mixture was filtered and the methanol evaporated; the residue was partitioned between ethyl acetate (100ml) and sodium hydrogen carbonate solution (120ml); the organic layer was washed with water (50ml) and dried with anhydrous magnesium sulphate before removal of the solvent. The unstable brown oil obtained was used in the next step without further purification. (S, R)-Methyl 4-[2-[(2-hydroxy-3-(2,3-diaminophenoxy)propyl)amino]-2- propyl]phenoxyacetate (1.42g, 3.52 mMol) was dissolved in aqueous hydrogen chloride (2 Molar, 30ml); to this was added a further 10ml of water. The solution was cooled to 5°C and phosgene bubbled through for 1 hour (with stirring). The mixture was then stirred overnight before being flushed out for 1 hour with a strong stream of nitrogen. The mixture was neutralised with solid sodium hydrogen carbonate and extracted with dichloromethane (2 x 30ml).The resulting solution was dried with magnesium sulphate and the solvent evaporated. The crude material was purified by chromatography over normal phase silica using 1 - 12% methanol in dichloromethane, to give the title compound as beige crystals of m.p. = 105-7°C. δ 1 H(400MHz, d 6 -DMSO): 7.17(2H, d, J=8.63Hz); 6.90-6.85(3H, m); 6.63(2H, dd, J=9.05, 8.49Hz); 4.72(2H, s); 4.16(1H, s br); 4.07(2H, d, J=5.63Hz); 3.72(3H, s); 3.31(1H, s br); 3.20(1H, d poorly resolved, J=10.29Hz); 2.63(1H, dd, J=13.32, 9.45Hz); 1.14(3H, d, J=6.42Hz). Example 2 (S R) 4-(2-[2-Hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazoI- 4- yloxy)propylamino]propyl)phenoxy)acetic acid, sodium salt (4-(2-[2-Hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazol-4- yloxy)propylamino]propyl)phenoxy)acetic acid, methyl ester (0.136g, 0.32 mMol) was dissolved in 1,4-dioxan (5ml) and treated with 2M aqueous sodium hydroxide solution (5ml). After stirring at room temperature for 22 hours, the dioxan was evaporated and diluted with water (5ml); the solution was adjusted to pH9, by addition of solid carbon dioxide. Chromatography on reverse phase silica eluting initially with water, then 10% isopropanol in water gave the title compound as beige coloured crystals of m.p. > 245°C (decomp). δ 1 H(400MHz, CD3OD/D2O 1:1): 7.13-7.04(3H, complex multiplet); 6.83(1H, d, J=7.42Hz); 6.78(2H, d, J=6.86Hz); 6.70(1 H, d, J=8.26Hz); 4.32(2H, s); 4.08(2H, dd, J=7.21, 3.45Hz); 4.03(1H, t, J=5.62Hz); 2.91(1H, q, J=6.57Hz); 2.85(1H, d, J=2.19Hz); 2.68-2.57(2H, complex multiplet); 1.07(3H, d, J=6.26Hz). Example 3 (S R) 4-[2-Hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazol-4- yIoxy)propylamino]p diethyl ester The title compound was prepared by an analogous procedure to that described in Example 1 from (S, R)-diethyl 4-[2-[2-hydroxy-3-(2-amino-3- nitrophenoxy)propylamine] -2-propyl]phenoxymethylphosphonate(0.99g, 1.94mMol), ammonium formate (l.OOg, 15.87mMol) and 10% Palladium on charcoal (250mg) in methanol (75ml). The mixture was stirred overnight at room temperature, filtered and the methanol evaporated. The residue was partitioned between ethyl acetate (70ml) and sodium bicarbonate solution (30ml), and finally the organic extracts were dried and the solvent evaporated. The resultant, unstable brown, oil was dissolved in aqueous 2M hydrochloric acid (35ml) and cooled to 5° C; phosgene gas was passed through the solution. After 2 hours the excess phosgene was removed by purging the solution with a strong stream of argon. The solvent was then evaporated and the resultant solid partitioned between ethyl acetate (160ml) and sodium bicarbonate solution (60ml). The organic layer was dried and evaporated. The crude material was purified by column chromatography over C\% silica e luting with 0-12% methanol in dichloromethane. δ 1 H(400MHz, d^-DMSO): 10.71(1H, exchanges with D 2 O); 10.54(1H, exchanges with D 2 O); 7.11(2H, d, J=8.6Hz): 6.91(2H, d, J=8.7Hz); 6.85(1H, d, J=8.1Hz); 6.61-6.57(2H, complex multiplet): 4.88(2H, exchanges with D2O); 4.35(2H, d, J=9.7Hz); 4.09(4H, m); 4.00(1 H, complex multiplet); 3.90(2H, complex multiplet); 2.85-2.66(4H, complex multiplet): 2.45(1H, complex multiplet); 1.25(6H, t, J=7.0Hz); 0.93(3H, d, J=6.1Hz). Example 4 (S R) 4-[2-Hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazoI-4- yloxypropylamino]propyl)phenoxymethylphosphonic acid ethyl ester lithium salt The title compound was prepared by an analogous method to that described in Example 2 from (S, R) 4-(2-[2-hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazol-4- yloxy)propyl)amino]propylphenoxymethylphosphonic acid, diethyl ester (1 lOmg, 0.22mMol) and 1M lithium hydroxide (10ml) in 1,4-dioxan (10ml) at room temperature for 24 hours under argon. The solution was adjusted to pH 9 by addition of solid carbon dioxide, and the solvents evaporated. The residue was purified by reverse phase chromatography over Cjg silica eluting with 0-10% isopropanol in water to give a white powder. δ 1 H(400MHz, CD 3 OD/D 2 O) 7.15-7.05(3H, complex multiplet); 6.87-6.76(3H, Two doublets, J=8.0Hz for both); 6.68(1H, d, J=8.3Hz); 4.10(2H, br multiplet); 4.05- 3.95(5H, complex multiplet); 2.95-2.77(3H, complex multiplet); 2.73-2.52(2H, complex multiplet); 1.24(3H, t, J=7.1Hz); 1.08(3H, d, J=6.2Hz). Example 5 (SR SS) 4-(2-[2-Hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazoI-4-yloxy) propylamino]propyl)ρhenoxymethylphosphonic acid 3-benzyloxypropyl ester Me A mixture of (S)-4-(3-amino-2-hydroxypropoxy)-2-oxo-2,3-lH-benzoimidazole (165mg, 0.74mMol), 4-(2-oxopropyl)phenoxymethylphosphonic acid 3-benzyloxypropyl ester (290mg, 0.74mMol) and palladium on carbon (200mg) in methanol (20ml) was hydrogenated at 50psi hydrogen and 50°C for 24 hours. The reaction mixture was filtered through celite and the solvent evaporated to yield a dark oil. FAB MASS SPEC MH + =510 Pharmacological Data: The activity of the present compounds may be tested by use of the following procedures: Agonist Activity at Rat βj and β2 Adrenoceptors In Vitro βj-Adrenoceptor Agonism: Female Sprague-Dawley rats (150-250g) are killed by a blow to the head and exsanguinated. Spontaneously beating right atria are removed by the method of Broadley and Lumley (1977) and mounted on a glass tissue holder. Each tissue is placed in 30 ml organ baths at 37°C containing Kreb's- Henseleit solution. Each atrium is attached to an isometric transducer by cotton and placed under an initial resting tension of lg. Rate recordings from the spontaneous beating atria are obtained from the tension signal using a Lectromed Type 4522 ratemeter. All traces are recorded on a Lectromed M4 chart recorder, β-adrenoceptor agonists are then added to the Krebs medium in a cumulative fashion and the results expressed as a percentage increase in atrial rate. β2-Adrenoceptor Agonism: Rat uterine horns are removed and bisected longitudinally. Each tissue is tied to a glass tissue holder and placed in Krebs- Henseleit solution in a 30 ml organ bath as before. Tissues are placed under a resting tension of lg and allowed to equilibrate. Each uterine strip is pre-contracted by the addition of 40mM K + to the bath to produced a steady tonic contraction, β-agonists are then added to the bath in a cumulative manner and results expressed as percentage inhibition of contraction. Agonist EC50 (atria) and IC50 (uteri) are calculated as the concentration of agonist producing 50% of their maximum increase in atrial rate or uterine relaxation. Relative intrinsic activity expressed as the maximal responses to test agonists relative to isoprenaline (=1.0) in both atria and uteri. References K.J. Broadley & P. Lumley (1977) Br. J. Pharmacol.52.51 Antagonist and Agonist Activity at Human β j , β 2, and β 3-Adrenoceptors. Subclones of CHO cells were stably transfected with each of the human βi, β 2 and β 3-adrenoceptors . Cells were then disrupted by immersion in ice-cold lysis buffer (10 mM TRIS, 2mM EDTA , pH 7.4) containing protease inhibitors leupeptin and benzamidine (5 μg/ ml) and soyabean trypsin inhibitor (10 μg/ ml). Membranes were prepared by the method of Bouvier et. al. 2 and stored in 1 ml aliquots in liquid N2 for future use. β 3-Adrenoceptor- Mediated Adenylyl Cyclase Activity Adenylyl cyclase activity was assayed by the method of Kirkham et. al.3 by the addition of 40 μl (70 -80 μg protein) to the incubation medium of the above CHO cell plasma membranes transfected with the human β3-adrenoceptor . cAMP produced over 20 minutes was separated from ATP by the method of Salomon et al. 4 . Agonist EC50 values and intrinsic activities were expressed as the concentration of agonist producing 50 % activation of adenylyl cyclase and the maximum response produced by each agonist relative to that produced by (-) isoprenaline respectively. EC 50 (uM) Example (4) β 3 0.9 Antagonist Binding at Displacement of cell plasma membranes transfected with either the human β j , or β 2-adrenoceptors was carried out by the method of Blin et. alA Ki values (nM) were calculated from the binding IC50 values for each agonist, using the Cheng -Prusoff equation. Ki(nM) Example (4) βi 3,620 β 2 460 References 1. T. Frielle et. al., Proc. Natl. Acad. Sci., 1987, 84, 7920; B. Kobilka, Proc. Natl. Acad. Sci., 1987, 84, 46; S. Liggett and D. Schwinn, DNA Sequence, 1991, 2, 61. 2. M. Bouvier et. al., Mol. Pharmacol, 1987, 33, 133. 3. D. Kirkham et. al., Biochem. J., 1992, 284, 301. 4. Y. Salomon et al., Anal. Biochem., 1974, 58, 541. 5. N. Blin, et. al., Br. J. Pharmacol., 1994, 112, 911.

Claims: Claims 1. A compound of formula (I): (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein, R° represents a moiety of formula (a): -0 0 * (a) wherein one of X or X 2 represents NH and the other of X* or X 2 represents NH, O or S and T represents hydrogen or one, two or three substitutents selected from the list consisting of: hydroxy, amino, alkylamino, dialkylamino, alkylsulphonamido, arylsulphonamido, amidoformyl, halogen and alkoxy; X represents O or S; R and R^ a each independently represents hydrogen or an alkyl group; R 2 represents OCH2CO2H, or an ester or amide thereof, or R 2 represents a moiety of formula (b): -0-CH 2 -P-OR 4 R 5 (b) wherein R 4 represent hydrogen, alkyl, hydroxyalkyl or cycloalkyl and R^ represent hydroxy, alkoxy, hydroxyalkyloxy or cycloalkyloxy or R^ represents hydrogen, alkyl, substituted alkyl, cycloalkyl or aryl or R^ together with OR 4 represents O(CH2) n O wherein n is 2, 3 or 4; and R3 represents hydrogen, halogen, alkyl or alkoxy or R^ together with R 2 represents a moiety of formula (c): (c) or an ester or amide thereof. 2. A compound according to claim 1, wherein χ and X 2 each independently represents NH. 3. A compound according to claim 1 or claim 2, wherein T represents hydrogen. 4. A compound according to any one of claims 1 to 3, wherein R 2 represents OCH2CO2H, or an ester or amide thereof. 5. A compound according to any one of claims 1 to 3, wherein R 2 represents a moiety of formula (b). 6. A compound according to claim 5, wherein R^ represents hydroxy, alkoxy, hydroxyalkyloxy or cycloalkyloxy. 7. A compound according to claim 5 or claim 6, wherein R 4 represents Ci _6 alkyl and R^ represents Cj.β alkoxy. 8. A compound according to any one of claims 1 to 7, wherein, R is an alkyl group and R^ a represents hydrogen. 9. A compound according to claim 1, being: (S,Rμ-(2-[2-hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazol-4- yloxy)propylamino]propyl)phenoxy)acetic acid, methyl ester, S,R) 4-(2-[2-hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazol- 4- yloxy)propylamino]propyl)phenoxy)acetic acid; (S,R 4-[2-hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazol-4- yloxy)propylamino]propyl)phenoxymethylphosphonic acid, diethyl ester, and especially, (S, R) 4-[2-hydroxy-3-(2-oxo-2,3-dihydro-lH-benzoimidazol-4- ylox\ ropylamino]propyl)phenoxymethylphosphonic acid, ethyl ester, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. 10. A compound according to any one of claims 1 to 7, wherein with reference to formula (I), the asymmetric carbon atom corresponding to that indicated by a single asterisk (*) is in the S-configuration and the asymmetric carbon atom corresponding to that indicated by two asterisks (**) is in the R-configuration. 11. A process for the preparation of a compound of formula (I), or a salt thereof or a solvate thereof, which process comprises: a) reacting a compound of formula (II) with phosgene: (ID wherein R , R a , R 2 , R3 and X are as defined in relation to formula (I) in claim 1, one of χ3 or X 4 represents NH2 and the other of X^ or X 4 is selected from NH2, OH or SH and T represents T as is defined in relation to formula (I) or a protected form thereof; or b) for preparing compounds of formula wherein R^ a is hydrogen, by reducing a compound of formula (XIII): (XIII) wherein R°, R , R3 and X are as defined in relation to formula (I) and R 2 ' represents R 2 as defined in relation to formula (I) or a protected form thereof; and thereafter, if necessary, carrying out one or more of the following optional steps: (i) converting one compound of formula (I) to another compound of formula (I); and (ii) removing any protecting group; and (iii) preparing a pharmaceutically acceptable salt thereof of a compound of formula (I) or a pharmaceutically acceptable solvate thereof. 12. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor. 13. A compound of formula (I), or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof, for use as an active therapeutic substance. 14. A compound of formula (I), or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof, for use in the treatment of hyperglycaemia, obesity, atherosclerosis, hyperinsulinaemia, gastrointestinal disorders or the treatment of gastrointestinal ulcerations. 15. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment of hyperglycaemia, obesity, atherosclerosis, hyperinsulinaemia, gastrointestinal disorders or the treatment of gastrointestinal ulcerations. 16. A method for treating hyperglycaemia, obesity, atherosclerosis, hyperinsulinaemia, gastrointestinal disorders or the treatment of gastrointestinal ulcerations in a human or non-human mammal, which comprises administering an effective, non-toxic, amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof, to the human or non-human mammal in need thereof. 17. A method for increasing weight gain and/or improving the feed utilisation efficiency and/or increasing lean body mass and/or decreasing birth mortality rate and increasing post/natal survival rate; of livestock, which method comprises the administration to livestock of an effective non-toxic amount of a compound of formula (I) or a veterinarily acceptable salt thereof; or a veterinarily acceptable solvate thereof. 18. A veterinarily acceptable premix formulation comprising a compound of formula (I), or a veterinarily acceptable salt thereof; or a veterinarily acceptable solvate thereof, in association with a veterinarily acceptable carrier therefore. 19. An intermediate: a) of formula (II): (II) wherein R , Rl a , R 2 , R 3 and X are as defined in relation to formula (I), one of X 3 or X 4 represents NH2 and the other of X 3 or X 4 is selected from NH2, OH or SH and T * represents T as defined in relation to formula (I) or a protected form thereof; or b) of formula (XIII): wherein R°, Rl, R 3 and X are as defined in relation to formula (I) and R 2 ' represents R 2 as defined in relation to formula (I) of claim 1 or a protected form thereof.

Inventors: BEELEY LEE JAMES, BERGE JOHN MICHAEL, BEELEY, LEE, JAMES, BERGE, JOHN, MICHAEL
Applicants: BEELEY LEE JAMES, BERGE JOHN MICHAEL, SMITHKLINE BEECHAM PLC, BEELEY, LEE, JAMES, BERGE, JOHN, MICHAEL
Application year: 1994
Main classification: C07D235
IPC codes: A61K31, A61P1, A61P3, A61P9, A61P25, C07C217, C07D235, C07D263, C07D277, C07F9